CN103896917B - A kind of process for purification of Esomeprazole sodium - Google Patents
A kind of process for purification of Esomeprazole sodium Download PDFInfo
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- CN103896917B CN103896917B CN201210581178.0A CN201210581178A CN103896917B CN 103896917 B CN103896917 B CN 103896917B CN 201210581178 A CN201210581178 A CN 201210581178A CN 103896917 B CN103896917 B CN 103896917B
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- esomeprazole sodium
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- sulfone
- crude product
- acetone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The present invention refines Esomeprazole sodium crude product using the method for mixed solvent recrystallization, and this method is easy to operate, product purity is high, single contaminant content is low（Sulfone ＜ 0.1%）, high income, more suitable for industrialized production Esomeprazole sodium process for purification.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical fields, and in particular to a kind of process for purification of Esomeprazole sodium.
Background technology
Esomeprazole sodium（Esomeprazole sodium）, the entitled S-5- methoxyl groups -2- of chemistry [（4- methoxyl group -3,
5- dimethyl -2- pyridyl groups）Methyl] sulfinyl } -1H- benzimidazole sodium is the first application researched and developed by Astrazeneca AB
In the single enantiomer S- of clinical proton pump inhibitor Omeprazole（-）The sodium salt of-Omeprazole.The medicine is mainly used for stomach and bursts
The treatment of ulcer, duodenal ulcer, peptic esophagitis and gastritis.Compared with Omeprazole, this product has strong and lasting
Sour inhibitory action, also have certain protective role to stomach lining, be the choice drug of current treatment gastric acid related disease.It is domestic
Outer many document reports its preparation method, but the document for being related to specific process for purification is less.
Esomeprazole sodium is refined with acetone as solvent merely in international monopoly WO03/089408, while adds in 0.7%
Sodium chloride solution to remove impurity sulfone, but acetone is smaller to the dissolubility of Esomeprazole sodium, Esso in the method subtractive process
U.S. draws azoles sodium complete always molten, it is impossible to effectively remove impurity, the sulfone only ＜ 0.2% in product, even if secondary refining can not be by sulfone
Less than 0.1% is dropped to, while the presence of a small amount of water makes the color of product deeper.
The content of the invention
In order to solve the above-mentioned technical problem, the present invention gropes by many experiments, have found it is a kind of it is easy to operate, product is pure
Degree is high, single contaminant content is low（Sulfone ＜ 0.1%）, high income, more suitable for industrialized production Esomeprazole sodium it is refined
Method.
This method comprises the following steps：
1）Dissolving：Esomeprazole sodium crude product is dissolved in mixed solvent A and B, is heated to reflux to Esomeprazole sodium
Quan Rong；
2）Crystallization：Slow cooling adds in crystal seed, continues to be cooled to temperature T while stirring to 20~60 DEG C1For -20~10
DEG C, soaking time t1For 1~10h；
3）Filtering, drying；
In the mixed solvent A is alcohols solvent, preferably one or more of methanol, ethyl alcohol, normal propyl alcohol, isopropanol；B is ketone
One or more of class or esters solvent, preferably acetone, 2- butanone, ethyl acetate, isopropyl acetate.
If for subtractive process merely with A, the solubility of Esomeprazole sodium is big, but the solubility is affected by temperature smaller, temperature
It is more difficult to control crystallization；If merely with B, the solubility of Esomeprazole sodium is too small, and solvent usage amount is excessive, and increase is refined into
This, and be unfavorable for removing impurity sulfone therein.So groping by experiment, the preferable mixed solvent of above-mentioned refining effect is obtained.
Mixed solvent dosage is：Esomeprazole sodium crude product：A：B=1：1：5~15（w/v/v）, preferred Esomeprazole sodium
Crude product：Methanol：Acetone=1：1：5~15（w/v/v）Or Esomeprazole sodium crude product：Ethyl alcohol：Acetone=1：1：5~15（w/v/v）,
Further preferred Esomeprazole sodium crude product：Ethyl alcohol：Acetone=1：1：10.
T1Preferably 0~10 DEG C；
t1Too short, crystallization is incomplete, causes the reduction of Esomeprazole sodium yield, t1Long, excessive impurity absorption is crystallizing
On, cause the purity of Esomeprazole sodium to reduce, therefore t1Preferably 1~10h；
Cooling rate in Crystallization Process is controlled in 10-60 DEG C/h, and cooling rate is too fast, and gained particle is larger, dissolving bag
It is mingled with matter, cooling rate is too slow, and the easy adsorbing contaminant of crystallization influences product purity.
In the course of dissolution, activated carbon can also be added in after Esomeprazole sodium crude product is dissolved, flowed back
30min after heat filter, continues the 2nd）Step.
The crystal seed is preferably the Esomeprazole sodium that optical purity and content are all higher than 99.9%；
The step 3）In filter, dry, can meet for conventional filtration drying method.
The present invention has following significant advantage compared with previous literature：
1st, product purity is high, and the content of impurity sulfone drops to less than 0.1%, and other lists are miscellaneous to be also respectively less than 0.1%, total miscellaneous to be less than
0.2%, the quality of gained Esomeprazole sodium meets Esomeprazole sodium import standard JX20080210；
2nd, by adjusting the ratio of in the mixed solvent A and B, to seek refined balance between yield and purity, production is ensured
On the premise of quality, make refined yield higher, up to more than 85%；
3rd, method for crystallising provided by the present invention, it is simple and easy to control, it is suitble to big production, cost is relatively low.
Specific embodiment
The following examples will be further explained the present invention, but the present invention includes but not limited to these implementations
Example, these embodiments do not limit the scope of the invention in any way.Those skilled in the art institute within the scope of the claims
Some be altered or modified made also is regarded as belonging to the scope of the present invention.
Embodiment 1
In the three neck round bottom flask of 1000mL, Esomeprazole sodium crude product 50.0g is added in（HPLC：98.9%, sulfone：
0.6%, ee%：99.4%）., the mixed solvent of methanol 50mL and acetone 250ml is added in, agitating and heating, reflux 0.5h solids are entirely molten,
It is slightly cold, activated carbon 1.0g is added in, 30min is stirred at reflux, filters while hot, filtrate slow cooling adds in crystal seed, stir to 35~45 DEG C
Mix be cooled to 0~10 DEG C of crystallization 6 it is small when, filtering, the washing filter cake of acetone 50mL × 2, filter cake 35~45 DEG C/- 0.095MPa vacuum
When drying 12 is small, Esomeprazole sodium 42.7g is obtained, refines yield：85.4%, HPLC：99.9%, sulfone：0.06%, ee%：99.8%,
Quality meets Esomeprazole sodium import standard JX20080210.
Embodiment 2
In the three neck round bottom flask of 2000mL, Esomeprazole sodium crude product 50.0g is added in（HPLC：98.7%, sulfone：
0.7%, ee%：99.4%）, the mixed solvent of methanol 50mL and acetone 750ml is added in, agitating and heating, reflux 1.5h solids are entirely molten,
It is slightly cold, activated carbon 1.0g is added in, 30min is stirred at reflux, filters while hot, filtrate slow cooling adds in crystal seed, stir to 35~45 DEG C
Mix be cooled to -10~0 DEG C of crystallization 5 it is small when, filtering, the washing filter cake of acetone 50mL × 2, filter cake 35~45 DEG C/- 0.095MPa vacuum
When drying 12 is small, Esomeprazole sodium 43.1g is obtained, refines yield：86.2%, HPLC：99.8%, sulfone：0.05%, ee%：99.7%,
Quality meets Esomeprazole sodium import standard JX20080210.
Embodiment 3
In the three neck round bottom flask of 2000mL, Esomeprazole sodium crude product 50.0g is added in（HPLC：99.0%, sulfone：
0.4%, ee%：99.5%）, the mixed solvent of methanol 50mL and acetone 500ml is added in, agitating and heating, reflux 2.5h solids are entirely molten,
It is slightly cold, activated carbon 1.0g is added in, 30min is stirred at reflux, filters while hot, filtrate slow cooling adds in crystal seed, stir to 35~45 DEG C
Mix be cooled to 0~10 DEG C of crystallization 6 it is small when, filtering, the washing filter cake of acetone 50mL × 2, filter cake 35~45 DEG C/- 0.095MPa vacuum
When drying 12 is small, Esomeprazole sodium 44.0g is obtained, refines yield：88.0%, HPLC：99.9%, sulfone：0.06%, ee%：99.9%,
Quality meets Esomeprazole sodium import standard JX20080210.
Embodiment 4
In the three neck round bottom flask of 1000mL, Esomeprazole sodium crude product 50.0g is added in（HPLC：99.1%, sulfone：
0.5%, ee%：99.2%）, the mixed solvent of ethyl alcohol 50mL and acetone 250ml is added in, agitating and heating, reflux 0.5h solids are entirely molten,
It is slightly cold, activated carbon 1.0g is added in, 30min is stirred at reflux, filters while hot, filtrate slow cooling adds in crystal seed, stir to 35~45 DEG C
Mix be cooled to -15~-5 DEG C of crystallizations 8 it is small when, filtering, the washing filter cake of acetone 50mL × 2,35~45 DEG C/- 0.095MPa of filter cake is true
When sky dry 12 is small, Esomeprazole sodium 44.6g is obtained, refines yield：89.2%, HPLC：99.8%, sulfone：0.04%, ee%：
99.7%, quality meets Esomeprazole sodium import standard JX20080210.
Embodiment 5
In the three neck round bottom flask of 2000mL, Esomeprazole sodium crude product 50.0g (HPLC are added in：98.8%, sulfone：
0.7%, ee%：98.9%) mixed solvent of ethyl alcohol 50mL and acetone 750ml, is added in, agitating and heating, reflux 2h solids are entirely molten, slightly
It is cold, activated carbon 1.0g is added in, 30min is stirred at reflux, filters while hot, filtrate slow cooling adds in crystal seed, stirring to 35~45 DEG C
Be cooled to -5~5 DEG C of crystallizations 4 it is small when, filtering, the washing filter cake of acetone 50mL × 2, filter cake 35~45 DEG C/- 0.095MPa vacuum does
It is dry 12 it is small when, obtain Esomeprazole sodium 44.4g, refine yield：88.8%, HPLC：99.7%, sulfone：0.05%, ee%：99.7%, matter
Amount meets Esomeprazole sodium import standard JX20080210.
Embodiment 6
In the three neck round bottom flask of 2000mL, Esomeprazole sodium crude product 50.0g is added in（HPLC：99.3%, sulfone：
0.4%, ee%：99.3%）, the mixed solvent of ethyl alcohol 50mL and acetone 500ml is added in, agitating and heating, reflux 2h solids are entirely molten, slightly
It is cold, activated carbon 1.0g is added in, 30min is stirred at reflux, filters while hot, filtrate slow cooling adds in crystal seed, stirring to 35~45 DEG C
Be cooled to 0~10 DEG C of crystallization 6 it is small when, filtering, the washing filter cake of acetone 50mL × 2, filter cake 35~45 DEG C/- 0.095MPa vacuum does
It is dry 12 it is small when, obtain Esomeprazole sodium 44.9g, refine yield：89.8%, HPLC：99.9%, sulfone：0.06%, ee%：99.9%, matter
Amount meets Esomeprazole sodium import standard JX20080210.
Embodiment 7
In the three neck round bottom flask of 2000mL, Esomeprazole sodium crude product 50.0g is added in（HPLC：98.7%, sulfone：
0.7%, ee%：99.2%）, add in the mixed solvent of methanol 50mL and 2- butanone 750ml, agitating and heating, reflux 2.5h solids are complete
It is molten, it is slightly cold, activated carbon 1.0g is added in, 30min is stirred at reflux, filters while hot, filtrate slow cooling adds in brilliant to 35~45 DEG C
Kind, stirring be cooled to 0~10 DEG C of crystallization 6 it is small when, filtering, the washing filter cake of 2- butanone 50mL × 2,35~45 DEG C of filter cake/-
When 0.095MPa vacuum drying 12 is small, Esomeprazole sodium 42.8g is obtained, refines yield：85.6%, HPLC：99.8%, sulfone：
0.07%, ee%：99.8%, quality meets Esomeprazole sodium import standard JX20080210.
Embodiment 8
In the three neck round bottom flask of 1000mL, Esomeprazole sodium crude product 50.0g is added in（HPLC：99.0%, sulfone：
0.6%, ee%：99.2%）, add in ethyl alcohol 50mL and ethyl acetate 250ml mixed solvent, agitating and heating, reflux 2h solids it is complete
It is molten, it is slightly cold, activated carbon 1.0g is added in, 30min is stirred at reflux, filters while hot, filtrate slow cooling adds in brilliant to 35~45 DEG C
Kind, stirring be cooled to -15~5 DEG C of crystallizations 10 it is small when, filtering, the washing filter cake of ethyl acetate 50mL × 2,35~45 DEG C of filter cake/-
When 0.095MPa vacuum drying 12 is small, Esomeprazole sodium 43.2g is obtained, refines yield：86.4%, HPLC：99.9%, sulfone：
0.05%, ee%：99.8%, quality meets Esomeprazole sodium import standard JX20080210.
Embodiment 9
In the three neck round bottom flask of 1000mL, Esomeprazole sodium crude product 50.0g is added in（HPLC：99.3%, sulfone：
0.4%, ee%：99.4%）, the mixed solvent of normal propyl alcohol 50mL and acetone 250ml is added in, agitating and heating, reflux 2h solids are entirely molten,
It is slightly cold, activated carbon 1.0g is added in, 30min is stirred at reflux, filters while hot, filtrate slow cooling adds in crystal seed, stir to 35~45 DEG C
Mix be cooled to 0~10 DEG C of crystallization 6 it is small when, filtering, the washing filter cake of acetone 50mL × 2, filter cake 35~45 DEG C/- 0.095MPa vacuum
When drying 12 is small, Esomeprazole sodium 42.9g is obtained, refines yield：85.8%, HPLC：99.8%, sulfone：0.04%, ee%：99.8%,
Quality meets Esomeprazole sodium import standard JX20080210.
Embodiment 10
In the three neck round bottom flask of 2000mL, Esomeprazole sodium crude product 50.0g is added in（HPLC：99.0%, sulfone：
0.6%, ee%：99.5%）, the mixed solvent of isopropanol 50mL and ethyl acetate 500ml is added in, agitating and heating, flow back 2.5h solids
Quan Rong, it is slightly cold, activated carbon 1.0g is added in, 30min is stirred at reflux, filters while hot, filtrate slow cooling adds in brilliant to 35~45 DEG C
Kind, stirring be cooled to -5~5 DEG C of crystallizations 3 it is small when, filtering, the washing filter cake of ethyl acetate 50mL × 2,35~45 DEG C of filter cake/-
When 0.095MPa vacuum drying 12 is small, Esomeprazole sodium 43.1g is obtained, refines yield：86.2%, HPLC：99.9%, sulfone：
0.06%, ee%：99.8%, quality meets Esomeprazole sodium import standard JX20080210.
Embodiment 11
In the three neck round bottom flask of 2000mL, Esomeprazole sodium crude product 50.0g is added in（HPLC：99.1%, sulfone：
0.7%, ee%：99.3%）, add in ethyl alcohol 50mL and isopropyl acetate 500ml mixed solvent, agitating and heating, reflux 2h solids it is complete
It is molten, it is slightly cold, activated carbon 1.0g is added in, is stirred at reflux 30 minutes, filters while hot, filtrate slow cooling adds in brilliant to 35~45 DEG C
Kind, stirring be cooled to 0~10 DEG C of crystallization 6 it is small when, filtering, the washing filter cake of isopropyl acetate 50mL × 2,35~45 DEG C of filter cake/-
When 0.095MPa vacuum drying 12 is small, Esomeprazole sodium 43.3g is obtained, refines yield：86.6%, HPLC：99.7%, sulfone：
0.06%, ee%：99.8%, quality meets Esomeprazole sodium import standard JX20080210.
Claims (3)
1. a kind of process for purification of Esomeprazole sodium, this method comprises the following steps：
1）Dissolving：Esomeprazole sodium crude product is dissolved in mixed solvent ethyl alcohol and acetone, is heated to reflux to esomeprazole
Sodium is entirely molten；
2）Crystallization：Slow cooling adds in crystal seed, continues to be cooled to temperature T while stirring to 20 ~ 60 DEG C1For 0 ~ 10 DEG C, during heat preservation
Between t1For 1 ~ 10h；
3）Filtering, drying；
Wherein, the dosage of each substance is Esomeprazole sodium crude product：Ethyl alcohol：Acetone=1:1:10；
Cooling rate in the Crystallization Process is controlled in 10 ~ 60 DEG C/h.
2. a kind of process for purification of Esomeprazole sodium as described in claim 1, it is characterised in that：The crystal seed is optics
Purity and content are all higher than 99.9% Esomeprazole sodium.
3. a kind of process for purification of Esomeprazole sodium as claimed in claim 1 or 2, it is characterised in that：The course of dissolution
In, activated carbon is added in after Esomeprazole sodium crude product is dissolved, is flowed back, after heat filter, continues the 2nd）Step.
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| CN201210581178.0A CN103896917B (en) | 2012-12-27 | 2012-12-27 | A kind of process for purification of Esomeprazole sodium |
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| CN103896917B true CN103896917B (en) | 2018-06-05 |
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| CN112661744B (en) * | 2020-12-28 | 2023-01-20 | 北京悦康科创医药科技股份有限公司 | Purification method of esomeprazole sodium |
| CN112898272A (en) * | 2021-01-29 | 2021-06-04 | 海南葫芦娃药业集团股份有限公司 | Purification method for reducing omeprazole sodium impurity D |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102089296A (en) * | 2008-07-09 | 2011-06-08 | 力奇制药公司 | Process for preparation of esomeprazole sodium of high chemical purity and new forms of esomeprazole sodium |
| CN102351847A (en) * | 2011-09-21 | 2012-02-15 | 南京新港医药有限公司 | Industrial method for refining esomeprazole sodium salt |
| CN102584792A (en) * | 2012-01-06 | 2012-07-18 | 南京优科生物医药研究有限公司 | Method for preparing high-purity esomeprazole |
| CN102813651A (en) * | 2011-06-07 | 2012-12-12 | 成都国为医药科技有限公司 | Pharmaceutical composition containing esomeprazole sodium, and preparation method thereof |
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- 2012-12-27 CN CN201210581178.0A patent/CN103896917B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102089296A (en) * | 2008-07-09 | 2011-06-08 | 力奇制药公司 | Process for preparation of esomeprazole sodium of high chemical purity and new forms of esomeprazole sodium |
| CN102813651A (en) * | 2011-06-07 | 2012-12-12 | 成都国为医药科技有限公司 | Pharmaceutical composition containing esomeprazole sodium, and preparation method thereof |
| CN102351847A (en) * | 2011-09-21 | 2012-02-15 | 南京新港医药有限公司 | Industrial method for refining esomeprazole sodium salt |
| CN102584792A (en) * | 2012-01-06 | 2012-07-18 | 南京优科生物医药研究有限公司 | Method for preparing high-purity esomeprazole |
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